U.S. patent number 11,154,513 [Application Number 15/280,411] was granted by the patent office on 2021-10-26 for semifluorinated compounds.
This patent grant is currently assigned to NOVALIQ GMBH. The grantee listed for this patent is NOVALIQ GMBH. Invention is credited to Ralf Grillenberger, Frank Loscher, Dieter Scherer, Hartmut Voss.
United States Patent |
11,154,513 |
Scherer , et al. |
October 26, 2021 |
Semifluorinated compounds
Abstract
The present invention is directed to certain semifluorinated
compounds and to compositions comprising such compounds. The
invention further provides the use of the compounds and of the
compositions as medicaments for topical administration to the
eye.
Inventors: |
Scherer; Dieter (Laufen,
CH), Grillenberger; Ralf (Nuremberg, DE),
Loscher; Frank (Schriesheim, DE), Voss; Hartmut
(Schriesheim, DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
NOVALIQ GMBH |
Heidelberg |
N/A |
DE |
|
|
Assignee: |
NOVALIQ GMBH (Heidelberg,
DE)
|
Family
ID: |
1000005888407 |
Appl.
No.: |
15/280,411 |
Filed: |
September 29, 2016 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20170087101 A1 |
Mar 30, 2017 |
|
Foreign Application Priority Data
|
|
|
|
|
Sep 30, 2015 [EP] |
|
|
15187760 |
Oct 30, 2015 [EP] |
|
|
15192429 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F
9/0008 (20130101); A61K 9/0048 (20130101); C07C
17/266 (20130101); A61K 47/02 (20130101); A61K
31/02 (20130101); A61K 9/08 (20130101); C07C
17/266 (20130101); C07C 19/08 (20130101); A61K
31/02 (20130101); A61K 2300/00 (20130101) |
Current International
Class: |
A61K
31/02 (20060101); A61K 47/02 (20060101); C07C
17/266 (20060101); A61K 9/08 (20060101); A61F
9/00 (20060101); A61K 9/00 (20060101) |
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1126-1130, 1 page (Abstract Only). cited by applicant .
Wang, W., "Lyophilization and Development of Solid Protein
Pharmaceuticals," International Journal of Pharmaceutics, 2000,
203, 1-60. cited by applicant .
Wirta, David L. et al., "A Clinical Phase II Study to Assess
Efficacy, Safety and Tolerability of Waterfree Cyclosporine
Formulation for the Treatment of Dry Eye Disease," Ophthalmology,
2019 126:792-800. cited by applicant .
Wu et al., "Physicochemical characterization and aerosol dispersion
performance of organic solution advanced spray-dried cyclosporine A
multifunctional particles for dry powder inhalation aerosol
delivery," International Journal of Nanomedicine, 2013,
8:1269-1283. cited by applicant .
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pages (English Machine Translation). cited by applicant.
|
Primary Examiner: Lundgren; Jeffrey S
Assistant Examiner: Strong; Tori
Attorney, Agent or Firm: Hoxie & Associates LLC
Claims
The invention claimed is:
1. An ophthalmic composition comprising
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
and CF.sub.3--(CF.sub.2).sub.3--(CH.sub.2).sub.4--CH.sub.3.
2. The composition according to claim 1, wherein the composition
consists of the
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub-
.3 and the
CF.sub.3--(CF.sub.2).sub.3--(CH.sub.2).sub.4--CH.sub.3.
3. The composition according to claim 1, being in liquid form and
comprising at least 1 wt % of said compound
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
or from 1 wt % to 5 wt % of said compound
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3,
based on the total weight of the composition.
4. The composition according to claim 1, being formulated as a
clear liquid solution.
5. The composition according to claim 1 being substantially free
of: (a) a polymer, (b) a perfluorinated compound, and/or (c) a
dissolved pharmacologically active ingredient which is not a
semifluorinated alkane.
6. The composition of according to claim 1, wherein the composition
is in liquid form and consists essentially of the compound
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
in an amount from 1 wt % to 5 wt % and the compound
CF.sub.3--(CF.sub.2).sub.3--(CH.sub.2).sub.4--CH.sub.3 in an amount
up to 95 wt %, based on the total weight of the composition.
7. The composition according to claim 1, being in liquid form and
comprising from 1 wt % to 5 wt % of
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
and up to 95 wt % of
CF.sub.3--(CF.sub.2).sub.3--(CH.sub.2).sub.4--CH.sub.3, based on
the total weight of the composition.
8. The composition according to claim 7, being formulated as a
clear liquid solution.
9. The composition according to claim 8 being substantially free
of: (a) a polymer, (b) a perfluorinated compound, and/or (c) a
dissolved pharmacologically active ingredient which is not a
semifluorinated alkane.
10. The composition of according to claim 9, wherein the
composition consists essentially of the
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
and the CF.sub.3--(CF.sub.2).sub.3--(CH.sub.2).sub.4--CH.sub.3, and
optionally one or more lipophilic liquid constituents.
11. A kit comprising an ophthalmic composition according to claim 1
and a container for holding the composition, wherein said container
comprises a dropper which dispenses droplets having a volume of 8
to 15 .mu.L topically to a lacrimal sac, lower eyelid, eye surface,
or other ophthalmic tissue.
12. A method of treating a disease or condition of a patient in
need of such treatment, comprising administering the composition
according to claim 1 to the patient.
13. The method according to claim 12, wherein the disease or
condition is dry eye disease (keratoconjunctivitis sicca) or a
symptom or condition associated therewith; and/or Meibomian Gland
Dysfunction (MGD), or a symptom or condition associated
therewith.
14. The method according to claim 13, wherein the composition is
topically administered into the lacrimal sac, into the lower
eyelid, to an eye surface or to an ophthalmic tissue.
15. The method according to claim 12, wherein the disease or
condition is corneal damage.
16. A method of treating a disease or condition of a patient in
need of such treatment, comprising administering the composition
according to claim 10 to the patient.
17. The method according to claim 16, wherein the disease or
condition is dry eye disease (keratoconjunctivitis sicca) or a
symptom or condition associated therewith; and/or Meibomian Gland
Dysfunction (MGD), or a symptom or condition associated
therewith.
18. The method according to claim 16, wherein the disease or
condition is corneal damage.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority to European Patent
Application Nos. 15187760.2 filed Sep. 30, 2015, and 15192429.7
filed Oct. 30, 2015, each of which are incorporated by reference in
their entireties.
DESCRIPTION
Field
The present invention is in the field of semifluorinated compounds,
compositions thereof, and their use as a medicine in particular for
ophthalmic administration.
Background
Semifluorinated alkanes are compounds composed of at least one
non-fluorinated hydrocarbon segment and at least one perfluorinated
hydrocarbon segment. Linear, unbranched semifluorinated alkanes of
the general formula CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH,
wherein n and m are integers denoting the number of carbon atoms of
the respective segment are described for various applications, for
example commercially for unfolding and reapplying a retina, for
long-term tamponade as vitreous humour substitute (H. Meinert et
al., European Journal of Ophthalmology, Vol. 10(3), pp. 189-197,
2000), and as wash-out solutions for residual silicon oil after
vitreo-retinal surgery.
Semifluorinated alkanes of the formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3 are described in
other applications.
WO 2011/073134 discloses solutions of ciclosporin in a
semifluorinated alkanes of the formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3, optionally in the
presence of a co-solvent such as ethanol, wherein the
semifluorinated alkane functions as a liquid drug delivery vehicle
for ciclosporin for topical treatment of keratoconjunctivitis
sicca.
WO2014/041055 describes mixtures of semifluorinated alkanes of the
formula CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3 (which may
be alternatively expressed as F(CF.sub.2).sub.n(CH.sub.2).sub.mH).
These mixtures are described to be ophthalmically applicable as
tear film substitutes or for treating patients with dry eye
syndrome and/or meibomian gland dysfunction.
A nomenclature which is frequently used for semifluorinated
compounds having linear and unbranched segments is FnHm, wherein F
means a perfluorinated hydrocarbon segment, H means a
non-fluorinated segment, and n and m define the number of carbon
atoms of the respective segment. For example, F3H3 is used for
perfluoropropylpropane,
CF.sub.3(CF.sub.2).sub.2(CH.sub.2).sub.2CH.sub.3, i.e.
1-perfluoropropylpropane.
Semifluorinated alkanes of the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
however have not been described, in particular for ophthalmic
applications. It is therefore an object of the invention to provide
such compounds, in particular in respect of their use in
compositions, especially with utility in the field of ophthalmic
applications.
SUMMARY OF THE INVENTION
In a first aspect, the invention relates to compositions comprising
a semifluorinated compound characterized by the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5. Preferably, these compositions are in the
form of a liquid, wherein the compositions comprise at least 1 wt.
%, in particular from 1 wt. % to 5 wt. % of a compound
characterized by
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5.
In another aspect, the present invention relates to compositions
comprising said compounds in the form of clear, liquid solutions,
and also compositions which essentially consist of said compounds
and optionally one or more lipophilic liquid constituents.
In still another aspect, the invention provides the use of
compositions comprising said compounds for treatment of dry eye
disease and/or Meibomian Gland Dysfunction and any symptoms or
conditions associated therewith.
In a further aspect, the present invention provides a method for
treatment of dry eye disease and any symptoms or conditions
associated therewith, comprising administering said composition
topically to the lacrimal sac, into the lower eyelid, to an eye
surface or to an ophthalmic tissue.
In a yet further aspect, the present invention provides a kit
comprising compositions of the present invention held in a
container which comprises dispensing means adapted for topical
administration of the composition to the eye or ophthalmic
tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph depicting the relative evaporation time of
compositions consisting of the compounds
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
as a function of the percentage of the latter compound in the
composition (indicated by the solid circle and dotted line in the
graph), and the relative evaporation time of compositions
consisting of the compounds
CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
as a function of the percentage of the latter compound in the
composition (indicated by the transparent circle and dashed line in
the graph).
FIG. 2 is a graph depicting the refractive index determined for
compositions consisting of the compounds
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
as a function of the percentage of the latter compound in the
composition.
FIG. 3 is a graph depicting the refractive index determined for
compositions consisting of the compounds
CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
as a function of the percentage of the latter compound in the
composition.
FIG. 4 is a graph representing the corneal erosion size
measurements (mm.sup.2) over the course of three days of an Ex vivo
Eye Irritation Test (EVEIT) comparison of compositions comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3,
a hyaluronic standard reference and 0.01% BAC positive control.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect, the invention relates to a semifluorinated
compound characterized by the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5.
Particularly preferred compounds of the formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
are those in which n is 5 and m is 5 (i.e. formula
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3),
or wherein n is 3 or and m is 2 (i.e. formula
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3).
Other preferred compounds include
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.3--CH.sub.3,
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3,
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.1--CH.sub.3,
and
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.3--CH.sub.3.
Alternatively, the compounds of the invention may be also generally
be referred to as 2-perfluoroalkylalkanes, for instance, the
compound
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
may also be referred to as 2-perfluorohexyloctane, based on the
hydrocarbon alkane as the root.
The compounds feature a stereocenter at the 2-alkyl position. As
understood herein, the general formula encompasses both
enantiomers, enriched mixtures of the two enantiomers, as well as
the racemic mixture.
It has been found that compounds as defined above provide a number
of unexpected advantages, as outlined below. They are particularly
useful when provided as compositions such as for medical
applications, in particular for topical administration, such as
topical ophthalmic administration.
The present invention relates to compositions comprising these
semifluorinated compound characterized by the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
as defined above are preferably in the liquid form, for example
formulated to be administered as a liquid solution. In optional
embodiments, the compositions may be formulated to be administered
as a gel, suspension, microemulsion, or a spray. Preferably, the
compositions are provided in sterile form.
In a particularly preferred embodiment, compositions comprising a
semifluorinated compound characterized by the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5 is in a liquid form and comprises at least 1
wt. % of the compound, in particular from 1 wt. % to 5 wt. %, based
on the total weight of the composition. In other embodiments, the
composition may comprise between about 3 wt. % to 5 wt. %, or about
5 wt. % to 10 wt. %, or up to 25 wt. % of the compound based on the
total weight of the composition.
In one of the preferred embodiments, the composition as defined
above is formulated as a clear, liquid solution. In this context,
clear means the absence of dispersed solid or liquid particles
which cause turbidity. In other words, such clear solution is a
purely monophasic liquid system, except that minor and technically
irrelevant amounts of particulate impurities may be present.
Moreover, the composition is preferably formulated as a liquid
solution which exhibits a refractive index that is close to that of
water which is 1.333 at room temperature (RT). In a particularly
preferred embodiment, the refractive index of the liquid solution
is in the range of from about 1.30 to about 1.35 at 20.degree. C.,
as determined by refractometer.
The compositions as defined above may also comprise further
excipients as required or as useful, such as one or more acids,
bases, electrolytes, buffers, solutes, antioxidants, stabilizers,
and if required, preservatives. In one preferred embodiment, the
compositions as defined above are substantially free of water
and/or substantially free of a preservative, such as benzalkonium
chloride.
In another preferred embodiment, the composition of the invention
is formulated as clear liquid solution that is substantially free
of the following: (a) a polymer (b) a perfluorinated compound,
and/or (c) a dissolved pharmacologically active ingredient which is
not a semifluorinated alkane. In another embodiment, the
composition as described herein may be substantially free of a
pharmacologically active ingredient in any form and which is not a
semifluorinated alkane.
As understood herein, the term `substantially free` in reference to
a composition constituent refers to the presence of said
constituent in no more than trace amounts and that if present in
trace amounts the constituent provides no technical contribution to
the composition.
Examples of polymers which are preferably absent in the
compositions of the invention include silicone polymers
(polymerized siloxanes), polyether polymers and fluorinated or
perfluorinated derivatives thereof.
Examples of perfluorinated compounds, i.e. compounds in which all
the hydrogen atoms are replaced with fluorine, and which are
preferably absent in the compositions of the invention include
perfluoroalkanes such as perfluorodecalin, as well as halogenated
perfluoroalkanes such as perfluorooctylbromide.
The compositions of the invention that are in the form of a clear
liquid solution are also substantially free of a dissolved
pharmacological active ingredient which is not a semifluorinated
alkane. As used herein, the term "pharmacological active
ingredient" refers to any type of pharmaceutically active compound
or drug, i.e. one that produces a pharmacological effect and that
may accordingly be useful in the prevention, diagnosis,
stabilization, treatment, or generally speaking, the management of
a condition or disease.
The compounds of the invention as well as the compositions
comprising these, even if free of other pharmacologically active
ingredients, however have beneficial therapeutic effects at the
site of administration.
In a further preferred embodiment, the compositions of the
invention essentially consist of a compound characterized by the
general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5, and optionally, one or more lipophilic liquid
constituents. In a particular embodiment, the composition consists
essentially of either the compound
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
or
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3,
or a mixture thereof, and optionally one or more lipophilic liquid
constituents.
As used herein, the term "essentially consisting of" is so-called
closed language, meaning that only the mentioned constituents are
present. In contrast, the terms "comprise", "comprises" and
"comprising" are used herein as so-called open language, meaning
that further constituents may also be present.
The optional lipophilic liquid constituents are preferably
substantially non-water soluble and/or non-water miscible
excipients, for example oily excipients such as lipids,
triglyceride oils and any other oils that are physiologically
tolerated by the eye, or other semifluorinated alkanes such as in
the class belonging to the general formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3, wherein n and m
are integers independently selected from the range of 3 to 8, for
example, CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3 or
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3.
Such lipophilic liquid constituents may be present in the
composition in amounts up to about 25 wt. % or up to about 50 wt.
%, or 75 wt. % or 90 wt. %, 95 wt. % or 97 wt. % of the
composition, based on total weight of the composition.
In a further preferred embodiment, the composition according to the
present invention comprises or essentially consists of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and CF.sub.3--(CF.sub.2).sub.5--(CH.sub.2).sub.7--CH.sub.3; or of
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
and CF.sub.3--(CF.sub.2).sub.3--(CH.sub.2).sub.4--CH.sub.3
The compositions as defined above are preferably formulated to have
a dynamic viscosity of not more than 10 mPas, and preferably not
more than 4 mPas, as determined under standard ambient temperature
and pressure (25.degree. C., 1 atm). Preferably, the compositions
have a dynamic viscosity of between 1 and 4 mPas. The viscosity of
the compositions may be determined using any standard viscometer
device known in the art, such as a glass tube or capillary
viscometer.
The compounds characterized by the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5 and compositions thereof as described herein
may be used in medical applications, in particular for use in
ophthalmology, in particular in the topical administration to the
eye, such as to the lacrimal sac, into the lower eyelid, to an eye
surface or to any ophthalmic tissue or anatomy associated with the
eye that may be made available for topical administration.
In particular, the compounds of the invention are beneficial for
use in the treatment of diseases and conditions which would benefit
from stabilization of the tear film and tear film lipid layer and
lubrication of the eye surface. Thus, the compositions of the
present invention are especially suited in the treatment of dry eye
disease (keratoconjunctivitis sicca) and/or Meibomian Gland
Dysfunction (MGD) and any symptoms thereof or associated
therewith.
Dry eye disease, also known as keratoconjunctivitis sicca, can be
distinguished into two categories, namely aqueous deficient dry eye
disease and evaporative dry eye disease. These conditions are not
necessarily mutually exclusive. Aqueous deficient dry eye is
typically observed in patients suffering from Sjo gren syndrome, or
those suffering from a lacrimal gland insufficiency, lacrimal duct
obstruction or reflex hyposecretion. Evaporative dry eye disease on
the other hand has diverse root causes and is associated with
increased/abnormal evaporative loss of the tear film, for example
as a result of meibomian gland disorders, eyelid aperture
disorders, blinking disorders, or ocular surface disorders.
Symptoms of dry eye disease include dry, scratchy, gritty, sandy or
foreign body sensations in the eye; pain, soreness, stinging or
burning; itching, increased need for blinking, eye fatigue,
photophobia, blurry vision, redness and inflammation of the eye
tissue, excess mucus discharge and crusting/clotting, contact lens
intolerance, and excess reflex tearing.
Meibomian Gland Dysfunction (MGD) refers to a condition where the
meibomian glands do not secrete enough oil, or when the oily
secretion is of poor or abnormal quality. Often, the oil gland
openings may become plugged up and obstructed so that less oil is
secreted from the glands. The oil that is secreted from the glands
can be granular (crusty) or otherwise abnormal, and can cause
irritation to the eye. In the early stages, patients are often
asymptomatic, but if left untreated, MGD can cause or exacerbate
dry eye symptoms and eyelid inflammation. The oil glands become
blocked with thickened secretions. Chronically clogged glands
eventually become unable to secrete oil, which may result in
permanent changes in the tear film and dry eyes.
Symptoms of Meibomian Gland Dysfunction include dryness, burning,
itching, stickiness/crustiness, watering, light sensitivity, red
eyes, foreign body sensation, chalazion/styes or intermittent
blurry vision.
In a preferred embodiment of the invention, the compounds and
compositions thereof as described above are used for the topical
ophthalmic treatment of evaporative dry eye disease and/or
Meibomian Gland Dysfunction, and relief of any one of the symptoms
associated therewith.
In one embodiment of the invention, the ophthalmic composition
comprising of a semifluorinated compound characterized by the
general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5; or preferably, wherein n is 5 and m is 5
(i.e. formula
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3),
or wherein n is 3 or and m is 2 (i.e. formula
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3),
are used for the treatment of dry eye disease (keratoconjunctivitis
sicca) or a symptom associated therewith. In another embodiment,
such composition may be used for the treatment of Meibomian Gland
Dysfunction or a symptom associated therewith.
In further embodiments, the treatment of these conditions is
preferably carried out by a method of administering to a patient in
need thereof, an effective amount of a composition essentially
consisting of said semifluorinated alkane, and optionally one or
more lipophilic liquid constituents that are preferably
substantially non-water soluble and/or non-water miscible
excipients, for example oily excipient such as lipids, triglyceride
oils and any other oils that are physiologically tolerated by the
eye, or other semifluorinated alkanes such as in the class
belonging to the general formula
CF.sub.3(CF.sub.2).sub.n(CH.sub.2).sub.mCH.sub.3, wherein n and m
are integers independently selected from the range of 3 to 8, for
example, CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3 or
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3.
In a further preferred embodiment of the invention, the compounds
and compositions thereof as described above are used for the
topical ophthalmic treatment of corneal damage. Thus, said
compounds and compositions are actively supporting the corneal
healing process of corneal damage, such as corneal erosions.
The advantages of the compounds described above in the context of
their use according to the present invention are believed to relate
to their properties which are particularly suited for ophthalmic
applications. The close proximity of the refractive indices of the
compounds of the invention to that of water, means that there would
be no or minimal impact of a patient's vision subsequent to
administration, unlike ophthalmic compositions based on oily
carriers which can confer blurry vision on administration. The
generally low viscosity and low surface tension and in particular
their high wetting and spreading capabilities of these compounds
also ensures that they are rapidly accommodated and adapted on
administration over the surface of the eye.
As will be made clearer in the examples below, it was found that
the compounds and compositions thereof are biocompatible and
exhibit no apparent cytotoxic effects. Moreover, it has been
established that said compounds and their compositions are not only
well tolerated in the eye, but also provide a beneficial effect in
terms of lubrication of the eye and stabilization of the tear film,
in the form of relief in symptoms of patients having mild to
moderate symptoms associated with dry eye disease and/or Meibomian
Gland Dysfunction. Patients with dry eye disease and/or
dysfunctional meibomian glands often express opaque and thicker
meibum which can lead to an abnormal lipid layer in the tear film.
Without wishing to be bound to theory, it is believed that the
physico-chemical attributes of the compounds of the invention may
play a role in stabilizing the lipid layer of the tear film, such
as by solubilization of certain lipid components or improving the
fluidity of the lipid layer.
In a further aspect, the present invention provides a method for
treatment of dry eye disease and any symptoms or conditions
associated thereof comprising administering the compositions of the
present invention topically to the lacrimal sac, into the lower
eyelid, to an eye surface or to an ophthalmic tissue. Preferably,
said compositions can be administered to the eye or eye tissue up
to four times per day.
Furthermore, the invention provides a kit comprising any one of the
compositions as described above, and a container for holding said
composition. Said container preferably comprises a dispensing means
adapted for topical administration of the composition to an eye
sac, lower eyelid to an eye or ophthalmic tissue, such as an eye
dropper.
In a further preferred embodiment, the dispensing means comprises a
dropper of dimensions such as to dispense droplets having a volume
of about 8 to 15 .mu.L, preferably having a volume of about 8-12
.mu.l, more preferably having a volume of about 10 .mu.l. With a
small droplet volume, precise dosing to the eye can be achieved and
an excess amount of discharge of a substantial fraction of the
composition from the eye subsequent to administration can be
avoided.
EXAMPLES
Preparation of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
(2-Perfluorohexyl-octane. C.sub.14F.sub.13H.sub.17)
The compound
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
may be prepared as follows: radical addition of perfluorohexyl
iodide with 1-octene in the presence of a radical initiator (herein
perfluorohexyl iodide is mixed with 1-octene and a radical
initiator as AIBN and the obtained solution is maintained at
80.degree. C. for 30 min and cooled down), followed by reduction of
the resulting iodo adduct with hydride (i.e. LiALH.sub.4) or via
hydrogenation (i.e. catalytic hydrogenation in presence of a
catalyst such as Pd/C) to form 2-perfluorohexyl-octane, followed by
purification by fractional distillation. Other compounds of formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.su-
b.3 as defined above may be prepared analogously by this general
method.
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3:
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 2.17-2.33 (m, 1H, CH), 1.67-1.77
(m, 2H, CH.sub.2), 1.25-1.40 (m, 8H, CH.sub.2), 1.15 (d, 3H,
CH.sub.3), 0.90 (t, 3H, CH.sub.3).
Preparation of
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
(2-Perfluorobutyl-pentane, C.sub.9F.sub.9H.sub.11)
The compound
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
may be prepared according to the general method described above
with perfluorobutyl iodide and 1-pentene as the starting
materials.
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3:
.sup.1H-NMR (CDCl.sub.3, 400 MHz): 2.21-2.32 (m, 1H, CH), 1.68-1.74
(m, 2H, CH.sub.2), 1.45-1.55 (m, 2H, CH.sub.2), 1.12 (d, 3H,
CH.sub.3), 0.92 (t, 3H, CH.sub.3).
In Vitro Cytotoxicity Assay
The cytotoxicity of a composition comprising 1.3 wt. %
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and 95.8 wt. % CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 was
assessed by a cell growth inhibition test which predicts cytotoxic
or necrotic effects with good correlation to animal experiments and
high sensitivity.
The composition was extracted by cell culture medium (DMEM
supplemented with 10% FBS) under agitation for .about.24 hours. The
resulting extract was then incubated with mouse cell line L929
cells for 68-72 hours, before the protein content was analyzed
using a BCA (bicinchoninic acid) test as a measure for
cytotoxicity. No inhibition of cell growth or cell lysis was
observed.
An analogous in vitro cytotoxicity assay is conducted for a
composition comprising about 23.7 wt. %
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and about 75.6 wt. % F6H8.
Tear Film Analysis Studies
A composition comprising 98.3 wt. % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and 1.2 wt. % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
was tested in an observational study in patients with mild to
moderate evaporative dry eye disease. The clear colorless liquid
composition was provided in a 5 ml bottle equipped with a dropper
dimensioned to dispense droplets of .about.10 .mu.l per drop into
the eye sac. Patients wearing contact lenses were excluded from the
study. After informed consent had been obtained, patients were
advised to apply 3-4 drops, daily in both eyes, translating to a
daily dose of 30-40 .mu.l. Patients returned after 5-7 weeks for
follow-up. Clinical data for 29 patients were collected at baseline
and at the 5-7 week follow-up visit.
a) Tear Film Analysis
Tear film fluid and tear film stability improved over the study
period, as can be seen in the increase in Schirmer I and the TFBUT.
The retrospective statistical analysis is strengthening this
observation, as the difference in TFBUT at baseline and follow-up
is highly significant (paired two-sided t-test: p=0.0026 (right
eyes) and p=0.0006 (left eyes)). No changes were detected in tear
osmolarity.
The subjective dry eye questionnaire (Ocular Surface Disease Index,
OSDI) revealed that patient's subjective symptom severity decreased
after the use of the composition comprising 98.3 wt. % of
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and 1.2 wt. % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
over a 5-7 week period, as can be seen in the lower scores at
follow-up and the retrospective statistical analysis (paired two
sided t-test: p<0.0001).
TABLE-US-00001 Parameter Baseline Follow up Schirmer I (mm/5 min)/
10.7 + 3.7 16.3 + 8.9 Right eye TFBUT (sec) Right eye: 5.7 + 2.6
Right eye: 7.9 + 5.1 Left eye: 5.7 + 2.6 Left eye: 8.6 + 6.0
Osmolarity 315.7 + 12.8 311.4 + 14.7 OSDI 53.9 + 22.5 35.8 +
22.9
b) Corneal Staining (Oxford Grading Scheme)
Corneal fluorescein staining is an indicator of corneal damage
(loss of cell-to-cell junctions). The data indicate a reduction of
corneal damage after 5-7 weeks of treatment, as can be seen in the
shift of numbers of patients diagnosed with Grade 1 or 2 at
baseline towards Grade 0 at follow-up. This difference to the
initial level of damage was statistically significant, as shown by
Wilcoxon signed rank test: p=0.0013 (right eyes) and p=0.0041 (left
eyes).
TABLE-US-00002 Baseline (n = 29) Follow up (n = 28) Grade 0 Grade 1
Grade 2 Grade 0 Grade 1 Grade 2 Right eye (n) 8 (1) 16 4 25 2 1
Left eye (n) 8 (1) 16 4 19 9 0
c) Symptom Assessment by Physician
Patients were asked by the physician whether they currently suffer
from typical dry eye symptoms both at the baseline and at the
follow-up visit. As can be seen in the table below, a lower number
of DED-associated symptoms were reported after 5-7 weeks of
treatment.
TABLE-US-00003 Baseline Follow up Red eyes 25 9 Itching 21 10
Clotted eyes 9 2 Stringy mucous 4 1 Headache 2 1
d) Meibum Secretion Analysis
In a healthy eye, meibum is secreted from the meibomian glands as a
clear liquid. More opaque and thicker meibum is an indicator of
dysfunctioning meibomian glands. Patients' meibum was descriptively
examined at both the baseline and the follow-up visit. According to
the data obtained, meibum quality improved in a number of cases. In
seven cases, the treatment induced a reduction of expressible
meibum (changing from clear meibum to none).
TABLE-US-00004 Baseline Follow up Clear 20 17 Whitish 6 3 Thick 1 0
None 2 9
e) Safety Parameters
No changes were seen in either visual acuity or intraocular
pressure, indicating that the use of composition comprising 98.3
wt. % of CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and 1.2
wt. % of
CF.sub.3--(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
over 5-7 weeks is safe and does not interfere with these
ophthalmological parameters.
TABLE-US-00005 Baseline Follow up Visual acuity 0.8 (0.7-1.0) 0.9
(0.8-1.0) Intraocular pressure (mm 14.9 .+-. 2.6 14.6 .+-. 3.2
HG)
Differential Scanning Calorimetry
Differential Scanning Calorimetry (DSC 1, Mettler Toledo,
Greifensee, Switzerland) is used to characterize structure and
phase behavior of mixtures of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3. DSC was
employed to obtain data on transitions by temperature rising scans
with heating rate of 1.degree. C./min. Sealed standard aluminum
crucibles (40 .mu.l, Mettler Toledo) were used.
TABLE-US-00006 wt % CF.sub.3--(CF.sub.2).sub.5-- Melting transition
CH(CH.sub.3)--(CH.sub.2).sub.5-- .DELTA.H Onset Peak Endset
CH.sub.3 (J/g) (.degree. C.) (.degree. C.) (.degree. C.) 0 -36.57
-6.33 -4.53 -2.14 5.91 -33.36 -10.32 -7.99 -7.24 12.03 -29.42
-13.74 -10.44 -9.58 23.74 -24.09 -21.56 -15.38 -14.17 wt % Low
temperature transition CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--
.DELTA.H Onset Peak Endset (CH.sub.2).sub.5--CH.sub.3 (J/g)
(.degree. C.) (.degree. C.) (.degree. C.) 0 -0.69 -45.47 -40.37
-38.32 5.91 -0.56 -50.61 -45.77 -42.93 12.03 -0.44 -55.18 -48.58
-45.53 23.74 -0.19 -60.75 -54.39 -52
The presence of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
in a mixture of
CF.sub.3(CF.sub.2).sub.5--(CH.sub.2).sub.7--CH.sub.3(F6H8) resulted
in a significant reduction in the melting temperature. The melting
enthalpy is also decreased, which suggests that this
semifluorinated alkane does not crystallize. Such differences will
have a beneficial effect in respect of the application of this
compound to the eye as a tear film substitute or lubricant; for
example, in terms of its ability to mix with, and to modulate the
tear film lipid layer. Such effects can moreover be advantageously
tuned by varying the amounts of the compound which are added to
ophthalmic compositions.
DSC measurements of a series of mixtures of 23.74 wt. % of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 with
tetradecane (C14) was also performed. Data on transitions were
obtained with temperature rising scans (heating rates 0.2, 0.5 and
1.degree. C./min). Extrapolation to a heating rate of 0.degree.
C./min was used to determine endset temperatures while average from
the three measurements were used to determine onset temperatures. A
decrease in the melting enthalpy was observed, compared to mixtures
of tetradecane with pure
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, suggesting that
some of the tetradecane is dissolved in the liquid fraction of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and that this compound has a stronger solubilizing capacity
compared to CF.sub.3 (CF.sub.2).sub.5 (CH.sub.2).sub.7CH.sub.3.
Refractive Index and Evaporation Time
The evaporation time of mixtures of the semifluorinated alkane
CF.sub.3(CF.sub.2).sub.3(CH.sub.2).sub.4CH.sub.3(F.sub.4H.sub.5)
and
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
was evaluated. A droplet of 10 .mu.L volume of each mixture was
placed on a glass surface at room temperature. Time until
evaporation was recorded by video-monitoring.
TABLE-US-00007 CF.sub.3(CF.sub.2).sub.3
CF.sub.3--(CF.sub.2).sub.3-- Relative (CH.sub.2).sub.4CH.sub.3/
CH(CH.sub.3)-- Evaporation Evaporation Sample %
(CH.sub.2).sub.2--CH.sub.3/% time/s Time 1 99.95 0.00 304 1.00 2
96.85 2.99 302 0.998 3 0.00 95.13 322 1.064
It was observed that an increased amount of the compound
CF.sub.3--(CF.sub.2).sub.3--CH(CH.sub.3)--(CH.sub.2).sub.2--CH.sub.3
appears to increase the evaporation time of the mixture (see FIG.
1).
The evaporation time of mixtures of the semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3(F6H8) and
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
was evaluated analogously.
TABLE-US-00008 CF.sub.3(CF.sub.2).sub.5 CF.sub.3(CF.sub.2).sub.5--
Relative (CH.sub.2).sub.7CH.sub.3/ CH(CH.sub.3)-- Evaporation
Evaporation Sample % (CH.sub.2).sub.5--CH.sub.3/% time/s Time 1
99.84 0.16 13260 1 2 96.53 3.05 12960 0.97 3 26.3 64.1 9960
0.75
In contrast, it was unexpectedly observed that an increasing
percentage of the semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
significantly decreases the evaporation time of the mixtures (see
FIG. 1).
Thus, depending on the compound characterized by the general
formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5 and amount present in the mixture, it may
feasible to adapt and fine-tune the composition to the requirements
of the intended ophthalmic use, such as in terms of prolonging or
reducing the residence time of the composition on the eye
surface.
The refractive index of the mixtures was also determined. For
topically applied ophthalmic compositions, the refractive index of
the composition should preferably be similar, or adapted to that of
the eye and lens, for instance as close to that of physiological
tear fluid as possible. If the refractive index of a composition is
not similar, when applied to the surface of the eye, a patient may
experience blurring or impaired vision. It is observed, that the
amount of the compound
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
or has an effect on refractive index. FIG. 2 depicts an increasing
refractive index value with increased content of the
2-perfluorohexyl-octane in a mixture with 1-perfluorohexyl-octane.
FIG. 3 likewise depicts an increasing refractive index value with
increasing content of 2-perfluorobutyl-pentane in a mixture with
1-perfluorobutylpentane.
By varying the amount of these compounds, such as characterized by
the general formula
CF.sub.3--(CF.sub.2).sub.n--CH(CH.sub.3)--(CH.sub.2).sub.m--CH.sub.3
wherein n is an integer selected from 3 to 5 and m is an integer
selected from 1 to 5 in the mixture, it may also be feasible to
adapt the composition to the requirements of the intended
ophthalmic use, for instance adapting to a patient with altered
tear fluid composition and refractive index due to an eye condition
and/or age.
Ex vivo Eye Irritation Test (EVEIT)
A comparison in respect of corneal healing process was conducted
for two compositions comprising
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3, namely
compositions consisting of a mixture of the semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5(CH.sub.2).sub.7CH.sub.3 and
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
(Composition A with 0.17 wt. % of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and Composition B, with 64 wt. % of
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3)
with hyaluronic acid (HYLO-COMOD.RTM.) as a reference and 0.01% BAC
(benzalkonium chloride) as a positive control using an Ex Vivo Eye
Irritation Test (EVEIT), similar to as described in M. Frentz et
al, Altern. to Lab. Anim., 2008 (36) p 25-32; and N. Schrage et al,
Graefes Arch Clin Exp Ophthalmol 2012 (250), 1330-1340).
Method. Rabbit corneas were obtained and placed in an artificial
anterior ocular chamber which was gently filled with serum-free
minimal essential medium (Eagle's MEM) containing Earle's salts and
HEPES buffer for nutrition. The medium was constantly replenished
by a micropump to imitate the physiological condition of the eye.
The culture chambers were held at 32.degree. C. under normal air
without supplementary CO.sub.2 and >95% relative humidity. Five
corneas per test substance (n=5) were used except for the positive
control with which two corneas (n=2) were tested.
After 12 h of stabilization in the culture chamber, the corneas
were evaluated by microscopy and corneas with intact epithelium and
without opacities were selected. Four small abrasions (2.3-4.3
mm.sup.2) were applied to the surface of the selected corneas with
a cornea drill. All defects were monitored by fluorescein sodium
staining (0.17% aq. solution) and microscopy.
The test substances were administered one hour after induction of
the corneal erosion and were applied six times daily onto the apex
of the corneas (30-50 .mu.L every four hours). A soft-tipped
cannula, with continuous suction was placed on the lowest part of
the corneoscleral region within the culturing chamber to remove any
excess fluid. Experiments were terminated after 3 days of
application. Biomicroscopic images of the corneas were taken daily
to document the corneal healing process using a phase-contrast
microscope integrated camera (KY-F1030U, JVC, (Bad Vilbel, Del.)
mounted on a Z16 APO Microscope (Wetzlar, Del.)). All defects were
monitored by fluorescein sodium stains (0.17% aq. solution) with
yellow green fluorescence indicating the areas of epithelial
defects. Erosion sizes were determined using a software tool of the
microscope (DISKUS). At the end of the 3 days, the experiment was
terminated and all corneas were fixed in 3.7% formaldehyde and
stained with a hematoxylin-eosin dye for microscopic evaluation. To
monitor the metabolic activity of the cornea, glucose and lactate
concentrations were photometrically quantified in the outflow
medium from the artificial anterior chambers.
Results. Both mixtures of the semifluorinated alkanes (Composition
A and B as referenced above) were observed to have a similar
positive effect in respect of the corneal healing process after the
induction of corneal erosion as compared with the standard
reference hyaluronic acid composition (HYLO-COMOD.RTM.).
Corneal Erosion Size Measurements/Mean mm.sup.2 (SD)
TABLE-US-00009 Composition Day 0 Day 1 Day 2 Day 3 A (n = 5) 12.8
(0.98) 3.018 (0.89) 0 (0) 0 (0) B (n = 5) 12.23 (1.46) 3.59 (0.53)
0 (0) 0 (0) HYLO 12.13 (1.29) 3.11 (0.76) 0.01 (0.02) 0 (0) COMOD
.RTM. 0.01% BAC 11.57 (0.86) 5.91 (0.28) 8.74 (7.6) 17.46
(6.43)
Day 3 Histological Observations
TABLE-US-00010 Composition A (n = 5) Multilayered epithelium and
dense stroma in all corneas. Keratocytes are well formed and
arranged except if lost from initial erosion area. Descemet
membrane appears intact, endothelial cells are present. B (n = 5)
Healed epithelial layer with closed multilayer of epithelial cells.
Dense stroma and regular formed keratocytes although typically
reduced in number under the initial erosion area. Descemet membrane
and endothelial layer present without structural defects Hylo
Multilayered epithelium and dense stroma with regular Comod .RTM.
arranged and formed keratocytes except under the (reference)
initial erosion areas where keratocytes are totally lost in the
upper stroma. Descemet membrane and endothelial layer are present
without any defects in structure. 0.01% BAC Severe alterations of
the superficial cornea with (positive disintegration of whole
corneal structures; observation of control) distinct edema Reduced
staining of background substance indicating chemical alteration of
collagen Severe reduction in number of keratocyte cells which also
appear rounded and pycnotic. Descemet membrane is present with
intact endothelium
No significant differences in terms of a positive corneal healing
was noted between composition B comprising 64 wt. %, based on total
weight of the composition of semifluorinated alkane
CF.sub.3(CF.sub.2).sub.5--CH(CH.sub.3)--(CH.sub.2).sub.5--CH.sub.3
and composition A. With both compositions, as with the reference
composition, the mechanically induced epithelial erosions were
found to be significantly reduced and essentially absent after day
2 of treatment. FIG. 3 depicts the corneal erosion size
measurements of the tested compositions, reference and positive
controls for days 0-3 of the EVEIT experiment.
As noted in the table above, microscopic histological examination
of the cross-sections of the corneas after termination of the
experiment on day 3 revealed no significant remaining defects or
differences in the corneas treated with compositions A, B and the
reference HYLO-COMOD.RTM..
Furthermore, no corneal toxicity, based on the metabolic activity
as indicated by the glucose/lactate measurements was observed for
these compositions.
In significant contrast, the positive control comprising 0.01% of
the preservative BAC, a progressive increase of the induced
epithelial lesions was observed over the course of the three days
of the experiment.
* * * * *
References